Multiple sclerosis and intracellular cobalamin defect (MMACHC/PRDX1) comorbidity in a young male

Pollini, Luca; Tolve, Manuela; Nardecchia, Francesca; Galosi, Serena; Carducci, Claudia; Carlo, Emanuele Di; Carducci, Carla

doi:10.1016/j.ymgmr.2019.100560

Cited by 5 publications

(5 citation statements)

References 12 publications

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“…Our findings indicate that the clinical signs and symptoms of epi-cblC are similar to that of canonical cblC disease. This is in line with previous reports on epi-cblC [ 6 , 18 ]. A homozygous PRDX1 :c.515-1G > T genotype seems to correlate with a more severe clinical phenotype than an homozygous MMACHC :c.271dupA genotype.…”

Section: Discussionsupporting

confidence: 94%

“…Until now, nine epi-cblC patients have been reported, all of whom with a mono-allelic MMACHC epimutation and a MMACHC genetic variant affecting the other allele [ 6 , 18 ]. The PRDX1 :c.515-1G > T variant was found in patients with Caucasian origin [ 6 , 18 ] whereas the PRDX1 :c.515-2A > T variant was only detected in one patient of Japanese-Korean ancestry [ 6 ]. To our knowledge, we are describing the first instance of epi-cblC due to a bi-allelic MMACHC epimutation.…”

Section: Discussionmentioning

confidence: 99%

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PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations

et al. 2021

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Background The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported. Methods We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients. Results All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient’s fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients. Conclusions We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations

et al. 2021

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“…The cblG phenotype is inherited as an autosomal recessive and has clinical and biochemical heterogeneity (41,42). As shown in the proband, it has previously been reported that the cblG phenotype can be present with neurological symptoms (43)(44)(45)(46)(47). Komulainen-Ebrahim et al and Kripps et al observed the neurological symptoms as a result of methionine synthase deficiency, along with the need for early treatment to reduce the neurological symptoms (48,49).…”

Section: Discussionmentioning

confidence: 93%

Novel WDR62 and MTR Variants in a Patient With Autosomal Recessive Primary Microcephaly-2 With Polymicrogyria and Homocystinuria-Megaloblastic Anemia

et al. 2022

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Background: Autosomal recessive primary microcephaly-2 (MCPH2) is a rare genetic disorder with clinical and genetic heterogeneity. This study aimed to perform high-throughput whole-exome sequencing (WES) to facilitate the diagnosis of the genetic variants responsible for MCPH2 and the comorbidities. Materials and Methods: The WES was performed for a 3-year-old boy with primary microcephaly-2 and homocystinuria-megaloblastic anemia in a consanguineous family. Sequencing and variant calling was conducted by standard bioinformatics tools. Filtering was performed to prioritize novel variants. Finally, the effect of variants on the protein structure and function was assessed using web prediction tools. Results: Using WES, two novel homozygous variants and three novel homozygous variants were identified in the WDR62 and MTR genes as the causes of MCPH2 and homocystinuria-megaloblastic anemia in the affected child, respectively. These frameshift insertion variants are classified as pathogenic and affect the structure and feature of the WDR62 and MTR proteins by changing amino acid sequence and causing nonsense-mediated RNA decay (NMD). Conclusion: Magnetic resonance imaging (MRI) supported polymicrogyria and impaired cerebral cortical development in the affected child. WDR62 as a causative gene plays an essential role in cerebral cortical development, and its pathogenic disease-causing variants are considered as causing factors for MCPH2. Homocystinuria-megaloblastic anemia was a comorbidity associated with microcephaly in this patient, and its variants were confirmed by WES. Overall, performing WES is a necessary and accurate way to rapidly identify the exact causative genetic variants in MCPH2 and the homocystinuria-megaloblastic anemia and manage the disease.

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“…The incidence of cblC defect ranges from 1:46,000 to 1:200,000 in European and American countries [2] and varies hugely from 1:3,220 to 1:21,488 in China [3][4][5].The cblC defect is caused by variants in the MMACHC gene located in chromosome region 1p34.1 [6]. This defect impairs the conversion of cobalamin to methylcobalamin and adenosylcobalamin, resulting in the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA) [7]. Based on the age of onset, cblC defect has two distinct phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Value of amniotic fluid homocysteine assay in prenatal diagnosis of combined methylmalonic acidemia and homocystinuria, cobalamin C type

Chen

Liang

Zhang

et al. 2021

Orphanet J Rare Dis

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Background Combined methylmalonic acidemia and homocystinuria, cobalamin C type (cblC defect) is the most common inborn error of cobalamin metabolism, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability of biochemical method for the prenatal diagnosis of cblC defect, we conducted a retrospective study of our 10-year experience at a single center. Methods 248 pregnancies whose probands were diagnosed as cblC defect were referred to our center for prenatal diagnosis from January 2010 to December 2019. Prenatal data of Hcy levels determined by enzymatic cycling assay, acylcarnitine analysis using liquid chromatography tandem mass spectrometry, organic acid analysis using gas chromatography mass spectrometry, and genetic analysis by direct sequencing of 248 at-risk fetuses were retrospectively reviewed. Results For 2.0 and 16.0 μmol/L levels of Hcy AF samples, the relative errors were − 2.5% and 2.8%, respectively. The respective measurement uncertainties were 13.07% and 14.20%. For the 248 at-risk fetuses, 63 fetuses were affected and 185 fetuses were unaffected. Hcy level of 13.20 (6.62–43.30) μmol/L in 63 affected fetuses was significantly higher than that in 185 unaffected fetuses of 2.70 (0.00–5.80) μmol/L, and there was no overlap between the affected and unaffected groups. The diagnostic sensitivity and specificity of Hcy were 100% and 92.05%, respectively. The positive and negative predictive values of the combination of Hcy, propionylcarnitine (C3), ratio of C3 to acetylcarnitine (C2; C3/C2), methylmalonic acid (MMA), and methylcitric acid (MCA) were both 100%. Sixteen fetuses displayed inconclusive genetic results of MMACHC variants, in which seven fetuses were determined to be affected with elevated levels of Hcy, C3, C3/C2 and MMA, and their levels were 18.50 (6.70–43.30) μmol/L, 8.53(5.02–11.91) μmol/L, 0.77 (0.52–0.97), 8.96 (6.55–40.32) mmol/mol Cr, respectively. The remaining nine fetuses were considered unaffected based on a normal amniotic fluid metabolite profile. Conclusions Hcy appears to be another characteristic biomarker for the prenatal diagnosis of cblC defect. The combination of Hcy assay with acylcarnitine and organic acid analysis is a fast, sensitive, and reliable prenatal diagnostic biochemical approach. This approach could overcome the challenge of the lack of genetic analysis for families with at-risk cblC defect fetuses.

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Multiple sclerosis and intracellular cobalamin defect (MMACHC/PRDX1) comorbidity in a young male

Cited by 5 publications

References 12 publications

PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations

PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations

Novel WDR62 and MTR Variants in a Patient With Autosomal Recessive Primary Microcephaly-2 With Polymicrogyria and Homocystinuria-Megaloblastic Anemia

Value of amniotic fluid homocysteine assay in prenatal diagnosis of combined methylmalonic acidemia and homocystinuria, cobalamin C type

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